WO2022068878A1 - 一种抗肿瘤化合物及其制备方法和应用 - Google Patents

一种抗肿瘤化合物及其制备方法和应用 Download PDF

Info

Publication number
WO2022068878A1
WO2022068878A1 PCT/CN2021/121721 CN2021121721W WO2022068878A1 WO 2022068878 A1 WO2022068878 A1 WO 2022068878A1 CN 2021121721 W CN2021121721 W CN 2021121721W WO 2022068878 A1 WO2022068878 A1 WO 2022068878A1
Authority
WO
WIPO (PCT)
Prior art keywords
mixture
independently
racemate
meso
tautomer
Prior art date
Application number
PCT/CN2021/121721
Other languages
English (en)
French (fr)
Chinese (zh)
Inventor
张禹
朱忠远
花海清
李冰
李键
林圣超
李曦
申红霞
Original Assignee
映恩生物制药（苏州）有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MX2023003778A priority Critical patent/MX2023003778A/es
Priority to CA3195515A priority patent/CA3195515A1/en
Application filed by 映恩生物制药（苏州）有限公司 filed Critical 映恩生物制药（苏州）有限公司
Priority to KR1020237011470A priority patent/KR20230079085A/ko
Priority to AU2021354823A priority patent/AU2021354823A1/en
Priority to CN202310152789.1A priority patent/CN116239601B/zh
Priority to CN202211403184.7A priority patent/CN116199739A/zh
Priority to CN202180018263.3A priority patent/CN115175705A/zh
Priority to EP21874533.9A priority patent/EP4223318A1/en
Priority to CN202211407530.9A priority patent/CN115925796B/zh
Priority to JP2023520181A priority patent/JP2023551355A/ja
Priority to IL301793A priority patent/IL301793A/en
Publication of WO2022068878A1 publication Critical patent/WO2022068878A1/zh
Priority to US17/825,090 priority patent/US11685742B2/en
Priority to US17/828,433 priority patent/US11607459B1/en
Priority to US18/147,070 priority patent/US11952384B2/en
Priority to US18/187,935 priority patent/US20230331738A1/en
Priority to US18/495,455 priority patent/US20240132516A1/en
Priority to US18/506,610 priority patent/US20240174686A1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present application relates to the field of biomedicine, in particular to an anti-tumor compound and its preparation method and application.
  • camptothecin derivatives small cytotoxic molecules for antibody drug conjugates can be camptothecin derivatives, which have antitumor effects by inhibiting topoisomerase I. Camptothecin derivatives can be used in antibody drug conjugates (ADC). However, there is still a need for further development of camptothecin derivatives and ADC drugs with better efficacy and/or safety.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof , which may have one or more effects selected from the group consisting of: (1) having inhibitory activity against tumor cell proliferation in vitro; (2) having targeted inhibitory properties; (3) having plasma stability; (4) (5) Bystander Effect; (6) Anti-transporter transport ability; (7) In vivo tumor targeting ability; and (8) Good in vivo safety.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof A salt for use, wherein the compound comprises the structure of formula (II-A):
  • Ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein said Ring A is surrounded by 0 or at least 1 Substituent R 1a is substituted;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclyl, said Ring A is substituted with p L 2 that are not R n ;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, said Ring A is substituted with p L 2 ;
  • L 2 is -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect a ligand
  • each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, - OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O) R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O) R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • n are each independently selected from an integer of at least 0, and p is an integer of at least 1.
  • the present application provides a compound represented by general formula (II-Ex) or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • Ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein said Ring A is surrounded by 0 or at least 1 Substituent R 1a is substituted;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclyl, said Ring A is substituted with p L 2 that are not R n ;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, said Ring A is substituted with p L 2 ;
  • L 2 is -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect a ligand
  • each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, - OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O) R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O) R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • n are each independently selected from an integer of at least 0, and p is an integer of at least 1.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof
  • the salt used contains the structure of formula (II-C x ):
  • L is -L a -L b -L c -;
  • the -L a - is selected from the following group:
  • W is -(C(R wa )(R wb )) wn -
  • Y is -(OCH 2 CH 2 ) yn -O yp -
  • Z is -(C(R za )(R zb )) zn ;
  • wn is selected from an integer of at least 0,
  • yn is selected from an integer of at least 0 and yp is 0 or 1;
  • zn is selected from an integer of at least 0,
  • -Cyr- is selected from the group consisting of 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene , wherein the -Cyr- is unsubstituted or independently substituted with at least 1 substituent R cx ;
  • each Rwa , Rwb , Rza , Rzb, Rwx , Rzx , Rcx is independently hydrogen, protium , deuterium, tritium, halogen, -NO2 , -CN, -ORr , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O) R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC (O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic group optionally substituted by R r ;
  • each R r , R ra , R rb is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - is selected from the following group:
  • R L1 and R L2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • Ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein said Ring A is surrounded by 0 or at least 1 Substituent R 1a is substituted;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclyl, said Ring A is substituted with p L 2 that are not R n ;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, said Ring A is substituted with p L 2 ;
  • L 2 is -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect a ligand
  • each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, - OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O) R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O) R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • n are each independently selected from an integer of at least 0, and p is an integer of at least 1.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof
  • the salt used contains the structure of formula (II-Dx):
  • Ab is a ligand, and the average number of connections Na is an integer or decimal from 1 to 10;
  • L is -L a -L b -L c -;
  • the -L a - is selected from the following group:
  • W is -(C(R wa )(R wb )) wn -
  • Y is -(OCH 2 CH 2 ) yn -O yp -
  • Z is -(C(R za )(R zb )) zn ;
  • wn is selected from an integer of at least 0,
  • yn is selected from an integer of at least 0 and yp is 0 or 1;
  • zn is selected from an integer of at least 0,
  • -Cyr- is selected from the group consisting of 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene , wherein the -Cyr- is unsubstituted or independently substituted with at least 1 substituent R cx ;
  • each Rwa , Rwb , Rza , Rzb, Rwx , Rzx , Rcx is independently hydrogen, protium , deuterium, tritium, halogen, -NO2 , -CN, -ORr , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O) R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC (O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic group optionally substituted by R r ;
  • each R r , R ra , R rb is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - is selected from the following group:
  • R L1 and R L2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • Ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein said Ring A is surrounded by 0 or at least 1 Substituent R 1a is substituted;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclyl, said Ring A is substituted with p L 2 that are not R n ;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, said Ring A is substituted with p L 2 ;
  • L 2 is -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect a ligand
  • each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, - OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O) R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O) R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • n are each independently selected from an integer of at least 0, and p is an integer of at least 1.
  • the present application provides a compound represented by the general formula (II-F x ) or its tautomer, meso, racemate, enantiomer, and diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • the L x is L ax -L b -L c -;
  • the Lax - is selected from the following group:
  • R hal is iodine or bromine
  • W is -(C(R wa )(R wb )) wn -
  • Y is -(OCH 2 CH 2 ) yn -O yp -
  • Z is -(C(R za )(R zb )) zn ;
  • wn is selected from an integer of at least 0,
  • yn is selected from an integer of at least 0 and yp is 0 or 1;
  • zn is selected from an integer of at least 0,
  • -Cyr- is selected from the group consisting of 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene , wherein the -Cyr- is unsubstituted or independently substituted with at least 1 substituent R cx ;
  • each Rwa , Rwb , Rza , Rzb, Rwx , Rzx , Rcx is independently hydrogen, protium , deuterium, tritium, halogen, -NO2 , -CN, -ORr , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O) R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC (O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic group optionally substituted by R r ;
  • each R r , R ra , R rb is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - is selected from the following group:
  • R L1 and R L2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • Ring A is selected from the group consisting of 3- to 10-membered saturated or partially unsaturated heterocyclyl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein said Ring A is surrounded by 0 or at least 1 Substituent R 1a is substituted;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated carbocyclyl, said Ring A is substituted with p L 2 that are not R n ;
  • Ring A is a 3- to 10-membered saturated or partially unsaturated heterocyclyl group, said Ring A is substituted with p L 2 ;
  • L 2 is -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect a ligand
  • each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, - OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O) R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O) R, -N(R)SO 2 R, or a C 1-6 aliphatic group optionally substituted by R;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • n are each independently selected from an integer of at least 0, and p is an integer of at least 1.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof
  • Use salts that contain the structure of the following groups:
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof A useful salt, wherein the compound comprises the structure of formula (III-A):
  • X is -L 1 -CH 2 -C(O)-;
  • each of R 2 , R 3a , R 3b , R 4b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ) , -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or any of R optionally substituted C 1-6 aliphatic groups;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , - SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group;
  • n is selected from an integer of at least 1;
  • R 1 is -O- or -HN-
  • the present application provides a compound represented by general formula (III-E) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • X is -L 1 -CH 2 -C(O)-;
  • each of R 2 , R 3a , R 3b , R 4b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ) , -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or any of R optionally substituted C 1-6 aliphatic groups;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , - SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group;
  • n is selected from an integer of at least 1;
  • R 1 is -O- or -HN-
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof
  • the salt used contains the structure shown in formula (III-C):
  • L is -L a -L b -L c -;
  • the -L a - is selected from the following group:
  • W is -(C(R wa )(R wb )) wn -
  • Y is -(OCH 2 CH 2 ) yn -O yp
  • Z is -(C(R za )(R zb )) zn ,
  • wn is selected from an integer of at least 0,
  • yn is selected from an integer of at least 0 and yp is 0 or 1;
  • zn is selected from an integer of at least 0,
  • -Cyr- is selected from the group consisting of 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene , wherein the -Cyr- is unsubstituted or independently substituted with at least 1 substituent R cx ;
  • each Rwa , Rwb , Rza , Rzb, Rwx , Rzx , Rcx is independently hydrogen, protium , deuterium, tritium, halogen, -NO2 , -CN, -ORr , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O) R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC (O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic group optionally substituted by R r ;
  • each R r , R ra , R rb is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - is selected from the following group:
  • R L1 and R L2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • X is -L 1 -CH 2 -C(O)-;
  • each of R 2 , R 3a , R 3b , R 4b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ) , -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or any of R optionally substituted C 1-6 aliphatic groups;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , - SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group;
  • n is selected from an integer of at least 1;
  • R 1 is -O- or -HN-
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof
  • the salt used which comprises the structure shown in formula (III-D):
  • Ab is a ligand, and the average number of connections Na is an integer or decimal from 1 to 10;
  • L is -L a -L b -L c -;
  • the -L a - is selected from the following group:
  • W is -(C(R wa )(R wb )) wn -
  • Y is -(OCH 2 CH 2 ) yn -O yp
  • Z is -(C(R za )(R zb )) zn ,
  • wn is selected from an integer of at least 0,
  • yn is selected from an integer of at least 0 and yp is 0 or 1;
  • zn is selected from an integer of at least 0,
  • -Cyr- is selected from the group consisting of 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene , wherein the -Cyr- is unsubstituted or independently substituted with at least 1 substituent R cx ;
  • each Rwa , Rwb , Rza , Rzb, Rwx , Rzx , Rcx is independently hydrogen, protium , deuterium, tritium, halogen, -NO2 , -CN, -ORr , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O) R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC (O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic group optionally substituted by R r ;
  • each R r , R ra , R rb is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - is selected from the following group:
  • R L1 and R L2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • X is -L 1 -CH 2 -C(O)-;
  • each of R 2 , R 3a , R 3b , R 4b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ) , -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or any of R optionally substituted C 1-6 aliphatic groups;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , - SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group;
  • n is selected from an integer of at least 1;
  • R 1 is -O- or -HN-
  • the present application provides a compound represented by general formula (III-F) or its tautomer, meso, racemate, enantiomer, and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • the L x is L ax -L b -L c -;
  • the Lax - is selected from the following group:
  • R hal is iodine or bromine
  • W is -(C(R wa )(R wb )) wn -
  • Y is -(OCH 2 CH 2 ) yn -O yp
  • Z is -(C(R za )(R zb )) zn ,
  • wn is selected from an integer of at least 0,
  • yn is selected from an integer of at least 0 and yp is 0 or 1;
  • zn is selected from an integer of at least 0,
  • -Cyr- is selected from the group consisting of 6 to 10 membered arylene, 5 to 8 membered heteroarylene, 3 to 10 membered heterocyclylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene , wherein the -Cyr- is unsubstituted or independently substituted with at least 1 substituent R cx ;
  • each Rwa , Rwb , Rza , Rzb, Rwx , Rzx , Rcx is independently hydrogen, protium , deuterium, tritium, halogen, -NO2 , -CN, -ORr , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O) R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC (O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic group optionally substituted by R r ;
  • each R r , R ra , R rb is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - is selected from the following group:
  • R L1 and R L2 are each independently selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • X is -L 1 -CH 2 -C(O)-;
  • each of R 2 , R 3a , R 3b , R 4b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ) , -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or any of R optionally substituted C 1-6 aliphatic groups;
  • each R, R a , R b is independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , - SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group;
  • n is selected from an integer of at least 1;
  • R 1 is -O- or -HN-
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable form thereof Useful salts, wherein the Ligand Drug Conjugate comprises the structure of the following group:
  • the application provides the preparation of a compound of the application or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof
  • a method of a pharmaceutically acceptable salt comprising contacting a ligand Ab with a structure represented by formula (II-F x ) of the present application.
  • the application provides the preparation of a compound of the application or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof
  • a method of a pharmaceutically acceptable salt comprising contacting a ligand Ab with a structure represented by formula (III-F) of the present application.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the application or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present application provides a compound containing the present application or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof.
  • a pharmaceutically acceptable salt and/or the pharmaceutical composition of the present application in the preparation of a medicament for treating and/or preventing tumors.
  • Figures 1 to 16 respectively show the results of in vivo tumor inhibition by the compounds of the present application.
  • the term "ligand” generally refers to a macromolecular compound capable of recognizing and binding to an antigen or receptor associated with a target cell.
  • the role of the ligand can be to present the drug to the target cell population that binds to the ligand, including but not limited to protein hormones, lectins, growth factors, antibodies, or others that can bind to cells, receptors and/or antigens molecule.
  • the ligand can be represented as Ab, and the ligand antigen forms a bond with the connecting unit through the heteroatom on the ligand, which can be an antibody or an antigen-binding fragment thereof, and the antibody can be selected from chimeric antibodies, human-derived antibody, fully human, or murine; the antibody may be a monoclonal antibody.
  • the antibody may be an antibody targeting the following targets: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70 or EGFR.
  • the antibody may be an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45 (PTPRC), CD46, CD47 , CD49D (IT), I
  • cytotoxic drug generally refers to a toxic drug, which may have strong chemical molecules within tumor cells that disrupt their normal growth. Cytotoxic drugs can kill tumor cells at high enough concentrations.
  • the "cytotoxic drug” may include toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, radioisotopes (eg At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 ) , Sm 153 , Bi 212 , P 32 or radioisotopes of Lu), toxic drugs, chemotherapeutic drugs, antibiotics and nucleolysins, for example, can be toxic drugs, including but not limited to camptothecin derivatives, for example, can be The tree alkaloid derivative ixatecan (chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H
  • linker structure generally refers to a chemical structural fragment or bond with one end connected to a ligand and the other end to a cytotoxic drug. Other linkers can also be connected to the cytotoxic drug.
  • the direct or indirect linking of the ligands may refer to that the group is directly linked to the ligands through covalent bonds, or may be linked to the ligands through a linker structure.
  • the linker structure may be the structures shown in -L ax -L b -L c - and or -L a -L b -L c - described herein.
  • chemical fragments comprising acid-labile linker structures (eg, hydrazones), protease-sensitive (eg, peptidase-sensitive) linker structures, photolabile linker structures, dimethyl linker structures, or disulfide-containing linker structures may be used or bond as a linker structure.
  • acid-labile linker structures eg, hydrazones
  • protease-sensitive linker structures eg, peptidase-sensitive linker structures
  • photolabile linker structures eg, dimethyl linker structures
  • disulfide-containing linker structures may be used or bond as a linker structure.
  • the term "optionally linked to other molecular moieties" of a structure generally means that the structure is not linked to any other chemical structure, or that the structure is linked to one or more other chemical structures different from the structure (eg, the ligands described herein) are linked (eg, by chemical bonds, or by linker structures).
  • ligand-drug conjugate generally refers to a ligand linked to a biologically active cytotoxic drug through a stable linking unit.
  • ligand-drug conjugate may be an antibody-drug conjugate (antibody drug conjugate, ADC), and the ADC may refer to the combination of monoclonal antibodies or antibody fragments with biological Active cytotoxic drugs are linked.
  • antibody or antigen-binding fragment thereof generally refers to immunological binding reagents extending to all antibodies from all species, including dimeric, trimeric and multimeric antibodies; bispecific antibodies ; chimeric antibodies; fully human antibodies; humanized antibodies; recombinant and engineered antibodies and fragments thereof.
  • the term “antibody or fragment thereof” may refer to any antibody-like molecule having an antigen binding region, and the term includes fragments of small molecules such as Fab', Fab, F(ab') 2 , single domain antibodies (DABs), Fv, scFv (single chain Fv), linear antibodies, diabodies, etc.
  • antigen-binding fragment can refer to one or more fragments of an antibody that retain the ability to specifically bind an antigen.
  • fragments of full-length antibodies can be used for the antigen-binding function of antibodies. Techniques for making and using various antibody-based constructs and fragments are well known in the art.
  • the antibody may include: anti-HER2 (ErbB2) antibody, anti-EGFR antibody, anti-B7-H3 antibody, anti-c-Met antibody, anti-HER3 (ErbB3) antibody, anti-HER4 (ErbB4) antibody, anti-CD20 antibody, anti-CD22 antibody , Anti-CD30 Antibody, Anti-CD33 Antibody, Anti-CD44 Antibody, Anti-CD56 Antibody, Anti-CD70 Antibody, Anti-CD73 Antibody, Anti-CD105 Antibody, Anti-CEA Antibody, Anti-A33 Antibody, Anti-Cripto Antibody, Anti-EphA2 Antibody, Anti-G250 Antibody, Anti- One or more of MUCl antibody, anti-Lewis Y antibody, anti-TROP2 antibody, anti-Claudin 18.2 antibody, anti-VEGFR antibody, anti-GPNMB antibody, anti-Integrin antibody, anti-PSMA antibody, anti-Tenascin-C antibody, anti-SLC44A4 antibody or anti-Mesothel
  • chimeric antibody generally refers to an antibody in which the variable region of a murine antibody is fused with the constant region of a human antibody, which can alleviate the immune response induced by the murine antibody.
  • a hybridoma that secretes a mouse-specific monoclonal antibody can be established, and then the variable region gene can be cloned from the mouse hybridoma cell, and the constant region gene of the human antibody can be cloned according to the needs.
  • the human constant region gene is connected into a chimeric gene and inserted into an expression vector, and the chimeric antibody molecule can be expressed in a eukaryotic system or a prokaryotic system.
  • humanized antibody also known as CDR-grafted antibody
  • CDR-grafted antibody generally refers to the grafting of murine CDR sequences into the framework of human antibody variable regions, i.e. different Types of human germline antibody framework sequences produced in antibodies.
  • the heterologous reaction induced by chimeric antibodies can be overcome because they carry a large amount of murine protein components.
  • framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences.
  • the germline DNA sequences of the human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database.
  • monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies.
  • the antibodies or ligands described herein may be fully human monoclonal antibodies.
  • Related technologies for the preparation of fully human antibodies include: human hybridoma technology, EBV transformation of B lymphocytes, phage display technology, transgenic mouse antibody preparation technology, and single B cell antibody preparation technology.
  • CDR generally refers to one of the six hypervariable regions within the variable domain of an antibody that primarily contribute to antigen binding.
  • 6 CDRs are provided by Kabat E.A. et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242), Chothia et al., “Canonical Structures For the Hypervariable Regions of Immunoglobulins, "J. Mol. Biol. 196:901 (1987); and MacCallum et al., “Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography,” J. Mol. Biol. 262:732 (1996)).
  • CDR L1, CDR L2, CDR L3 or L1, L2, L3 the Kabat definition of CDRs can be applied to CDR1, CDR2 and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of the light chain variable domains, as well as the heavy chain variable domains of CDR1, CDR2 and CDR3 (CDR H1, CDR H2, CDR H3 or H1, H2, H3).
  • methylene generally refers to a residue derived from a group of 1 carbon atom by removing two hydrogen atoms. Methylene groups can be substituted or unsubstituted, substituted or unsubstituted.
  • alkylene generally refers to a saturated straight or branched aliphatic hydrocarbon group having 2 residues derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane, which It may be a straight or branched chain group containing from 1 to 20 carbon atoms, eg, an alkylene group containing from 1 to 12 carbon atoms, eg, containing from 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene ( -CH2- ), 1,1-ethylene (-CH( CH3 )-), 1,2-ethylene ( -CH2) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene ( -CH2CH2CH2- ), 1,4 - Butylene ( -CH2CH2CH2CH2- ) and 1,5 - Butylene ( -CH2CH2CH2CH2CH2- ) Wait.
  • Alkylene may be substituted or unsubstituted, substituted or non-substituted, for example when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy substituted by one or more substituents in the group, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo, such as hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2
  • arylene generally refers to a residue having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of an aromatic ring.
  • aromatic ring may refer to a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring (ie, rings that share adjacent pairs of carbon atoms) having a conjugated pi-electron system, and may be 6 to 10 membered, such as benzene and Naphthalene.
  • the aromatic ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring.
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , and heterocycloalkylthio.
  • heteroarylene generally refers to a residue having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a heteroaromatic ring.
  • heteromatic ring refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur and nitrogen.
  • Heteroaryl can be 5 to 10 membered, 5 membered or 6 membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazole Base et al.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • Heteroarylene may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkane Oxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, and heterocycloalkylthio.
  • the substituents are preferably one or more of the following groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, alkane Oxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • heterocyclylene generally refers to stable non-aromatic 3- to 7-membered monocyclic structures, fused 7- to 10-membered bicyclic heterocyclic structures or bridged 6- to 10-membered monocyclic structures.
  • Member bicyclic heterocyclic structures which may be either saturated or partially saturated, and which, in addition to carbon atoms, contain one or more heteroatoms, wherein the heteroatoms may be selected from the following groups : oxygen, sulfur and nitrogen. For example, it contains 1-4 heteroatoms as defined above.
  • nitrogen may include nitrogen that has undergone a substitution reaction.
  • Heterocyclylene groups can be substituted or unsubstituted.
  • carbocyclylene generally refers to a residue having two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a carbocyclic ring.
  • carrier generally refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon, the carbocycle contains 3 to 20 carbon atoms, may contain 3 to 12 carbon atoms, may contain 3 to 10 carbon atoms, may Contains 3 to 8 carbon atoms.
  • Non-limiting examples of monocyclic carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, cyclooctane etc.; polycyclic carbocycles may include spiro, fused and bridged carbocycles. Carbocyclylene can be substituted or unsubstituted.
  • partially unsaturated generally refers to a cyclic structure containing at least one double or triple bond between the ring molecules.
  • the term “partially unsaturated” encompasses cyclic structures with multiple unsaturations, but is not intended to include aromatic or heteroaromatic rings as defined herein.
  • the term “unsaturated” means that the moiety has one or more degrees of unsaturation.
  • halogen generally refers to fluorine, chlorine, bromine, iodine, and may be, for example, fluorine, chlorine.
  • aliphatic group generally refers to straight-chain, branched or cyclic hydrocarbons having 1 to 12 carbon atoms, either fully saturated; or with one or Multiple unsaturated units, but the unsaturated units are not aromatic groups.
  • suitable aliphatic groups may include substituted or unsubstituted linear, branched or cyclic structures of alkyl, alkenyl, alkynyl, and mixtures of these groups; such as (cycloalkyl)alkyl , (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • aliphatic groups have 1-12, 1-8, 1-6, 1-4, or 1-3 carbon atoms.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification may include both instances where the heterocyclic group is substituted with an alkyl group and where the heterocyclic group is not substituted with an alkyl group. situation.
  • substituted generally means that one or more hydrogen atoms in a group, eg up to 5, eg 1 to 3 hydrogen atoms, independently of one another, are substituted with the corresponding number of substituents.
  • Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the term 0 or more (eg, 0 or at least 1, 0 or 1, 0) methylene units "replaced” generally refers to when the structure contains 1 or more
  • One or more hydrogen atoms in the group are substituted by the corresponding number of substituents.
  • Substituents are only in their possible chemical positions, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort.
  • amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the term "compound” generally refers to a substance having two or more different elements.
  • the compound of the present application may be an organic compound.
  • the compound of the present application may be a compound with a molecular weight of 500 or less, a compound with a molecular weight of 1,000 or less, or a compound with a molecular weight of 1,000 or more, or a compound of 10,000 or more and 100,000 or more. compound.
  • a compound can also refer to a compound connected by chemical bonds, for example, it can be a compound in which one or more molecules with a molecular weight of less than 1000 are connected with a biological macromolecule by chemical bonds, and the biological macromolecule can be a polysaccharide, protein , nucleic acids, peptides, etc.
  • the compounds of the present application can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 1000, can include compounds in which proteins are linked to one or more molecules with a molecular weight of less than 10,000, and can include proteins and one or more molecular weights. Compounds with less than 100,000 molecules linked together.
  • structures described herein may also include compounds that differ only in the presence or absence of one or more isotopically enriched atoms.
  • the hydrogen atom is replaced by deuterium or tritium, or the carbon atom is replaced by carbon 13 or 1 carbon 14, the compounds whose structure is consistent with the present application are all within the scope of the present application.
  • the term "pharmaceutical composition” generally refers to a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other Such as physiological/pharmaceutically acceptable carriers and excipients.
  • the pharmaceutical composition can facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the preparation of conventional pharmaceutical compositions can be found in the Chinese Pharmacopoeia.
  • the term "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” generally refers to a salt of a compound or ligand-drug conjugate of the present application, or a salt of a compound described in the present application, which Such salts can be safe and/or effective when used in mammals, and can have due biological activity.
  • the antibody-antibody drug conjugate compounds of the present application can form salts with acids, non-pharmaceutically acceptable salts.
  • Limiting examples include: hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, citrate, acetate, succinate, ascorbate, oxalate, nitrate, pearic acid Salt, hydrogen phosphate, dihydrogen phosphate, salicylates, hydrogen citrate, tartrate, maleate, fumarate, formate, benzoate, mesylate, ethanesulfonate acid salt, benzene sulfonate, p-toluene sulfonate.
  • solvate or “solvate” generally refers to the ligand-drug conjugate compound of the present application forming a pharmaceutically acceptable solvate with one or more solvent molecules, non-limiting solvent molecules Examples include water, ethanol, acetonitrile, isopropanol, DMSO, ethyl acetate.
  • drug loading usually refers to the average amount of cytotoxic drug loaded on each ligand, and can also be expressed as the ratio of the amount of cytotoxic drug to antibody, and the cytotoxic drug loading can range from each ligand (Ab). ) linked 0-12, eg 1-10 cytotoxic drugs.
  • the drug loading is expressed as Na , which can be the mean value of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 exemplarily.
  • the drug loading of each ADC molecule after conjugation reaction can be characterized by conventional methods such as UV/Vis spectroscopy, mass spectrometry, ELISA assay and HPLC.
  • the pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any blended fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can also be used in the preparation of injectables.
  • the term "about” generally refers to a range of 0.5%-10% above or below the specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof Salts for use, wherein the compound may comprise the structure of formula (I-A):
  • L 2 can be -(C(R 3a )(R 3b )) m -R, and m can be selected from an integer of 1 or more;
  • L 1 can be -(C(R 5a )(R 5b )) n -, and n can be selected from an integer of 1 or more;
  • -Cy- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring group, wherein the -Cy- is unsubstituted or each independently may be substituted by 1 or more substituents R 7 ;
  • each of R 3a , R 3b , R 4 , R 5a , R 5b , R 6 can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N (R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O) R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R) SO 2 R, or a C 1-6 aliphatic group which may be optionally substituted by R, or R 3a and R 5a , R 4 and R 5a , R 3a and R 6 , or R 4 and R 6 are each independently any optionally substitute
  • each R 2 , R 7 , R 8 can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R , -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R , or can be any of R optionally substituted C 1-6 aliphatic groups;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (I-A):
  • L 2 can be -(C(R 3a )(R 3b )) m -R, and m can be selected from an integer of 1 or more;
  • L 1 can be -(C(R 5a )(R 5b )) n -, and n can be selected from an integer of 1 or more;
  • -Cy- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring group, wherein the -Cy- is unsubstituted or each independently may be substituted by 1 or more substituents R 7 ;
  • each of R 3a , R 3b , R 4 , R 5a , R 5b , R 6 can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N (R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O) R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R) SO 2 R, or a C 1-6 aliphatic group that may be optionally substituted by R;
  • each R 2 , R 7 , R 8 can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R , -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R , or can be any of R optionally substituted C 1-6 aliphatic groups;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or A pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (I-A),
  • R 3a and R 5a , R 4 and R 5a , R 3a and R 6 , or R 4 and R 6 each independently optionally together with the atoms between them, can form Ring B, which can Selected from the group consisting of 5- to 8-membered heteroarylene, and 3- to 10-membered saturated or partially unsaturated heterocyclylene, wherein the ring B is unsubstituted or may be substituted by more than 1 substituent R Substituted, each R 3a , R 3b , R 4 , R 5a , R 5b , R 6 can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, - N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O )
  • Ring B which can be selected from the group consisting of 5- to 8-membered heteroarylene, and 3- to 10-membered saturated or partially unsaturated
  • each of R 3b , R 4 , R 5b , R 6 may independently be hydrogen, protium, deuterium , Tritium, Halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O) R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N ( R a )(
  • Ring B which can be selected from the group consisting of 5- to 8-membered heteroarylene, and 3- to 10-membered saturated or partially unsaturated
  • each of R 3a , R 3b , R 5b , R 6 can be independently hydrogen, protium, deuterium , Tritium, Halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O) R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N ( R a )(
  • Ring B which can be selected from the group consisting of 5- to 8-membered heteroarylene, and 3- to 10-membered saturated or partially unsaturated
  • each of R 3b , R 4 , R 5a , R 5b may independently be hydrogen, protium, deuterium , Tritium, Halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O) R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N ( R a )
  • Ring B which can be selected from the group consisting of 5- to 8 -membered heteroarylene, and 3- to 10-membered A saturated or partially unsaturated heterocyclylene group, wherein the ring B is unsubstituted or may be substituted by one or more substituents R 8 , each of which R 3a , R 3b , R 5a , R 5b independently may be is hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C( O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ) , -SO
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (I-A):
  • R 1 can be -O-
  • L 2 may be -(C(R 3a )(R 3b )) m -R, and m may be selected from an integer from 1 to 3;
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer from 2 to 4;
  • each of R 3a , R 3b , R 5a , R 5b , R 6 can each independently be hydrogen, halogen, or a C 1-6 aliphatic group that can be optionally substituted by R, or R 3a and R 5a and their Atoms in between can form Ring B, which can be selected from a 5-membered saturated heterocyclylene, wherein said Ring B is unsubstituted,
  • R can be hydrogen or halogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (I-A):
  • R 1 can be -O-
  • L 2 may be -(C(R 3a )(R 3b )) m -R, and m may be an integer selected from 1 or 2;
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer of 2 or 3;
  • 0 or 1 methylene unit of L 1 can be replaced by -C(O)-;
  • each of R 3a , R 3b , R 5a , R 5b can each independently be hydrogen, or R 3a and R 5a together with the atoms between them can form a ring B, which can be selected from 5-membered saturated Heterocyclylene having 1 nitrogen heteroatom, wherein said Ring B is unsubstituted,
  • R can be hydrogen
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (I-A):
  • R 1 can be -O-
  • L 2 may be -(C(R 3a )(R 3b )) m -R, and m may be an integer selected from 1 or 2;
  • L 1 may be -(C(R 5a )(R 5b )) 2 -;
  • each of R 3a , R 3b , R 5a , R 5b can each independently be hydrogen, or R 3a and R 5a together with the atoms between them can form a ring B, which can be selected from 5-membered saturated Heterocyclylene having 1 nitrogen heteroatom, wherein said Ring B is unsubstituted,
  • R can be hydrogen
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or A pharmaceutically acceptable salt thereof, wherein the compound may comprise the structure of the following group:
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (II-A):
  • X 1 can be selected from the group consisting of N, P, and saturated or unsaturated C, when X 1 can be saturated C, the X 1 can be substituted by R n ;
  • the structure represented by the formula (II-A) is connected with other molecular moieties;
  • ring A When X 1 may be saturated C, ring A may be selected from the group consisting of a 3- to 10-membered saturated or partially unsaturated heterocyclyl, and a 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein The ring A may be substituted by 0 or more substituents R 1a ;
  • Ring A can be selected from the group consisting of: 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 10-membered partially unsaturated heterocyclyl, and 3 to a 10-membered partially unsaturated carbocyclyl, wherein the ring A may be substituted with 0 or more substituents R 1b ;
  • Ring A can be selected from the group consisting of 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated heterocyclyl, wherein Ring A can be Substituted by 0 or more substituents R 1c ;
  • Ring A can be selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated carbocyclyl, said Ring A can be separated by p L 2 is substituted, and the L 2 cannot be R n ;
  • Ring A when Ring A may be a 3- to 10-membered saturated or partially unsaturated heterocyclic group, the Ring A may be substituted with p L 2 , or the Ring A may contain q ring-forming heteroatoms X 2 And the X 2 is used to connect the structure represented by the formula (II-A) with other molecular moieties;
  • X 2 can be selected from the following group: N, and P;
  • L 2 can be -R 2 -L 3 -, and the R 2 is used to connect the structure represented by the formula (II-A) with other molecular moieties;
  • each of R 1a , R 1b , R 1c , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), - OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that may be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • n and n can each independently be selected from an integer of 0 or more, and p and q can each independently be selected from an integer of 1 or more.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ax):
  • X 1 may be saturated C, and X 1 may be substituted by R n ;
  • Ring A may be selected from the group consisting of a 3- to 10-membered saturated or partially unsaturated heterocyclyl, and a 3- to 10-membered saturated or partially unsaturated carbocyclyl, wherein the ring A may be composed of 0 or 1 more than one substituent R 1a is substituted;
  • the ring A can be substituted by p L 2 , p can be selected from an integer of 1 or more, and the L 2 cannot be R n ;
  • L 2 can be -R 2 -L 3 -;
  • L 3 may be -(C(R 3a )(R 3b )) m -, and m may be selected from an integer of 0 or more,
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer of 0 or more,
  • each R 1a , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 , R n independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O )R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O ) R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ay):
  • X 1 may be saturated C, and X 1 may be substituted by R n ;
  • Ring A may be a 3- to 10-membered saturated or partially unsaturated heterocyclic group, wherein the ring A may not be substituted or may be substituted with more than 1 substituent R 1a ;
  • the ring A may contain q ring-forming heteroatoms X 2 and the X 2 is used to directly or indirectly connect a ligand; q may be selected from an integer greater than 1, and X 2 may be selected from the group consisting of: N, and P;
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer of 0 or more,
  • each of R 1a , R 5a , R 5b , R 6 , and R n independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a ) (R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S (O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ax):
  • X 1 can be unsaturated C
  • Ring A may be selected from the group consisting of 6- to 10-membered aryl, 5- to 8-membered heteroaryl, 3- to 10-membered partially unsaturated heterocyclyl, and 3- to 10-membered partially unsaturated carbocyclyl, wherein The ring A can not be substituted or can be substituted by more than 1 substituent R 1b ;
  • the ring A may be substituted by p L 2 , and p may be selected from an integer of 1 or more;
  • L 2 can be -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect the ligand;
  • L 3 may be -(C(R 3a )(R 3b )) m -, and m may be selected from an integer of 0 or more,
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer of 0 or more,
  • each R 1b , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R ;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ay):
  • X 1 can be unsaturated C
  • Ring A may be a 3- to 10-membered partially unsaturated heterocyclic group, wherein the ring A is unsubstituted or may be substituted by more than one substituent R 1b ;
  • the ring A may contain q ring-forming heteroatoms X 2 and the X 2 is used to directly or indirectly connect a ligand; q may be selected from an integer greater than 1, and X 2 may be selected from the group consisting of: N, and P;
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer of 0 or more,
  • each R 1b , R 5a , R 5b , R 6 can independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or can be R optionally substituted C 1-6 aliphatic group;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ax):
  • X 1 can be N or P
  • Ring A may be selected from the group consisting of 5- to 8-membered heteroaryl, and 3- to 10-membered saturated or partially unsaturated heterocyclyl, wherein said Ring A may not be substituted or may be substituted by more than 1 substituent R 1c replaced;
  • the ring A may be substituted by p L 2 , and p may be selected from an integer of 1 or more;
  • L 2 can be -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect the ligand;
  • L 3 may be -(C(R 3a )(R 3b )) m -, and m may be selected from an integer of 0 or more,
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer of 0 or more,
  • each of R 1c , R 2a , R 3a , R 3b , R 4 , R 5a , R 5b , R 6 independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R ;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ay):
  • X 1 can be N or P
  • Ring A may be a 3- to 10-membered saturated or partially unsaturated heterocyclic group, wherein the ring A may not be substituted or may be substituted with more than 1 substituent R 1c ;
  • the ring A may contain q ring-forming heteroatoms X 2 and the X 2 is used to directly or indirectly connect a ligand; q may be selected from an integer greater than 1, and X 2 may be selected from the group consisting of: N, and P;
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from an integer of 0 or more,
  • each R 1c , R 5a , R 5b , R 6 can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or can be R optionally substituted C 1-6 aliphatic group;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ax):
  • X 1 may be saturated C, and X 1 may be substituted by R n ;
  • Ring A can be selected from the group consisting of 3- to 6-membered saturated heterocyclyl, and 3- to 6-membered saturated or partially unsaturated carbocyclyl;
  • p may be 1, and the L 2 may not be R n ;
  • L 2 can be -R 2 -L 3 -;
  • R 2 can be selected from -O-;
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from 0 or 1;
  • L 1 can comprise a methylene unit
  • each R 3a , R 3b , R 5a , R 5b , R n each independently can be hydrogen, halogen or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R can independently be hydrogen or halogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ax):
  • X 1 can be saturated C and said X 1 is attached to R n , which can be H;
  • Ring A may be selected from the group consisting of a 5-membered saturated heterocyclyl group having 1 nitrogen heteroatom, and a 4- to 6-membered saturated carbocyclyl group;
  • the p may be 1;
  • L 2 can be -R 2 -L 3 -, and the L 3 is directly connected to the ring A;
  • L 3 can be -(C(R 3a )(R 3b )) m -, and m can be 0 or 2;
  • R 2 can be -O-
  • L 1 can be -C(O)-
  • each of R 3a , R 3b can independently be hydrogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ay):
  • X 1 may be saturated C, and X 1 may be substituted by R n ;
  • Ring A can be a 3- to 6-membered saturated heterocyclyl
  • the ring A may contain 1 ring-forming heteroatom N and the N is used to directly or indirectly attach a ligand;
  • L 1 may be -(C(R 5a )(R 5b )) n -, and n may be selected from 0 or 1;
  • each of R 5a , R 5b , R n independently can be hydrogen, halogen or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R can independently be hydrogen or halogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ay):
  • X 1 may be saturated C, and X 1 may be substituted with H;
  • Ring A may be a 5-membered saturated heterocyclic group with 1 N heteroatom
  • the ring A may contain 1 ring-forming heteroatom N and the N is used to directly or indirectly attach a ligand;
  • L 1 may be -C(O)-.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ax):
  • X 1 can be unsaturated C
  • Ring A may be selected from the group consisting of 6-membered aryl, 5- to 8-membered heteroaryl, 3- to 10-membered partially unsaturated heterocyclyl, and 3- to 10-membered partially unsaturated carbocyclyl, wherein the ring A is not substituted or can be independently substituted by 1 substituent R 1b ;
  • the p may be 1;
  • L 2 can be -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect the ligand;
  • L 3 may be -C(R 3a )(R 3b )-;
  • R 2 can be selected from -O-, -(R 2a )N-, or -S-;
  • L 1 can be -C(R 5a )(R 5b )-;
  • each of R 1b , R 2a , R 3a , R 3b , R 5a , R 5b can each independently be hydrogen, halogen, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R can independently be hydrogen or halogen.
  • the compound may comprise the structure of formula (II-Ax):
  • X 1 can be unsaturated C
  • Ring A can be selected from the group consisting of 6-membered aryl, and 5- to 8-membered heteroaryl;
  • the p may be 1;
  • L 2 can be -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect the ligand;
  • L 3 may be -C(R 3a )(R 3b )-;
  • R 2 can be selected from -O-, -(R 2a )N-, or -S-;
  • L 1 can be -C(R 5a )(R 5b )-;
  • each of R 2a , R 3a , R 3b , R 5a , R 5b can each independently be hydrogen, halogen or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R can independently be hydrogen or halogen.
  • the compound may comprise the structure of formula (II-Ax):
  • X 1 can be unsaturated C
  • Ring A can be a 6-membered aryl group
  • the p may be 1;
  • L 2 can be -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect the ligand;
  • L 3 may be -C(R 3a )(R 3b )-;
  • R 2 can be -O-
  • L 1 can be -C(O)-
  • each of R 3a , R 3b , R 5a , and R 5b can each independently be hydrogen or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ay):
  • X 1 can be unsaturated C
  • Ring A may be a 5-membered partially unsaturated heterocyclyl
  • the ring A may contain 1 ring-forming heteroatom N and the N is used to directly or indirectly attach a ligand;
  • L 1 can be -C(R 5a )(R 5b ),
  • each R 5a , R 5b independently can be hydrogen, halogen or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R can independently be hydrogen, halogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ax):
  • X 1 can be N
  • Ring A can be a 6-membered saturated heterocyclyl
  • the p may be 1;
  • L 2 can be -R 2 -L 3 -, and said R 2 is used to directly or indirectly connect the ligand;
  • L 3 can be -(C(R 3a )(R 3b )) m -, m can be 1 or 2,
  • R 2 can be selected from the group consisting of -O-, -(R 2a )N-, and -S-;
  • L 1 may be -C(R 5a )(R 5b )-,
  • each of R 2a , R 3a , R 3b , R 5a , R 5b can each independently be hydrogen, halogen or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R can independently be hydrogen or halogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (II-Ay):
  • X1 can be N
  • Ring A may be a 5-membered partially unsaturated heterocyclyl
  • the ring A may contain 1 ring-forming heteroatom N and the N is used to directly or indirectly attach a ligand;
  • L 1 can be -C(R 5a )(R 5b ),
  • each R 5a , R 5b independently can be hydrogen, halogen or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R can independently be hydrogen, halogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or A pharmaceutically acceptable salt thereof, which may comprise the structure of the following group:
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound may comprise a structure represented by formula (III-A):
  • X may be selected from the group: -L 1 -C(R 1a )(R 1b )-C(O)-, -L 1 -C(R 1a )(R 1b )-C(S)-, -L 1 -L 0 -, and -L 3 -L 2 -;
  • each of R 1a , R 1b , R 2 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7a , R 7b , R 8 can be independently is hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C( O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ) , -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that may
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • n can be selected from an integer greater than 1;
  • R 1 can be -O- or -HN-
  • X can be -L 1 -CH 2 -C(O)-, wherein when L 1 can contain a methylene unit, more than one L 1
  • R 1 can be -O-
  • X can be -L 3 -C(O)-
  • 1 methylene unit of L 3 can be replaced by -NR 8
  • R 8 cannot be -CH 2 -CH 2 - NH 2 ;
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be selected from the group consisting of -O-, -(R 2 )N-, and -S-;
  • X may be -L 1 -C(R 1a )(R 1b )-C(S)-;
  • L 1 may be -(C(R 3a )(R 3b )) m -, and m may be selected from an integer greater than or equal to 0;
  • R 2 can be halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O )R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N (R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that may be optionally substituted by R;
  • each of R 1a , R 1b , R 3a , R 3b , R 4b can independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a ) (R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S (O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -S- or -(R 2 )N-;
  • X may be -L 1 -C(R 1a )(R 1b )-C(O)-;
  • L 1 may be -(C(R 3a )(R 3b )) m -, and m may be selected from an integer greater than or equal to 0;
  • R 2 can be halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O )R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N (R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that may be optionally substituted by R;
  • each of R 1a , R 1b , R 3a , R 3b , R 4b can independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a ) (R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R, -S (O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O- or -HN-
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 can be -(C(R 3a )(R 3b )) m -, and m can be selected from an integer of 1 or more;
  • each R 3a , R 3b , R 4b can independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), - C(O)R, -CO2R, -C (O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O ) 2R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or optionally by R Substituted C 1-6 aliphatic groups;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O- or -HN-
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 may be -(C(R 3a )(R 3b )) m -, and m may be selected from an integer greater than or equal to 0;
  • each R 3a , R 3b , R 4b can independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), - C(O)R, -CO2R, -C (O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O ) 2R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or optionally by R Substituted C 1-6 aliphatic groups;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-, -S- or -(R 2 )N-,
  • X can be -L 1 -L 0 -;
  • L 1 may be -(C(R 3a )(R 3b )) m -, and m may be selected from an integer greater than or equal to 0;
  • R 2 can be halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O )R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N (R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that may be optionally substituted by R;
  • each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N( R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R , -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -HN-
  • X can be -L 1 -L 0 -;
  • L 1 can be -(C(R 3a )(R 3b )) m -, m can be selected from an integer greater than or equal to 0, and each R 3a , R 3b may not be hydrogen at the same time;
  • each R 2a , R 2b , R 3a , R 3b , R 4a , R 4b can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N( R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R , -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R1 may be -S- or - (R2 ) N-, or R1 may be -O- and L2 may not be -C (O) - , or R1 may be -NH- and L2 may not be- C(O)-;
  • L 3 can be -(C(R 7a )(R 7b )) n -, and n can be selected from an integer of 1 or more;
  • R 2 can be halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O )R, -C(O)CH 2 C(O)R, -S(O)R, -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N (R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that may be optionally substituted by R;
  • each R 5a , R 5b , R 6 , R 7a , R 7b , R 8 can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N( R a )(R b ), -C(O)R, -CO 2 R, -C(O)C(O)R, -C(O)CH 2 C(O)R, -S(O)R , -S(O) 2 R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or a C 1-6 aliphatic group that can be optionally substituted by R;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 3 -L 2 -,
  • L 2 can be -C(O)-
  • L 3 may be -(C(R 7a )(R 7b )) n -, and n may be selected from an integer greater than or equal to 0;
  • each R 7a , R 7b , R 8 can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), - C(O)R, -CO2R, -C (O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O ) 2R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or optionally by R Substituted C 1-6 aliphatic groups;
  • R, R a , R b can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H , -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group,
  • R 8 cannot be a C 1-6 aliphatic group that can be substituted by -NH 2 .
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -HN-
  • X can be -L 3 -L 2 -;
  • L 2 can be -C(O)-
  • L 3 can be -(C(R 7a )(R 7b )) n -, and n can be selected from an integer of 1 or more;
  • each R 7a , R 7b , R 8 can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N(R a )(R b ), - C(O)R, -CO2R, -C (O)C(O)R, -C(O) CH2C (O)R, -S(O)R, -S(O ) 2R, -C(O)N(R a )(R b ), -SO 2 N(R a )(R b ), -OC(O)R, -N(R)SO 2 R, or optionally by R Substituted C 1-6 aliphatic groups;
  • each R, R a , R b independently can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 may be -O-, -S- or -(R 2 )N-;
  • X may be -L 1 -C(R 1a )(R 1b )-C(S)-;
  • L 1 may be -(C(R 3a )(R 3b )) m -, and m may be 0, 1 or 2;
  • each of R 1a , R 1b , R 2 , R 3a , R 3b can each independently be hydrogen or a C 1-6 aliphatic group optionally substituted by R;
  • each R can be hydrogen
  • the compound may comprise the structure of formula (III-A):
  • R 1 can be -O-
  • X may be -L 1 -C(R 1a )(R 1b )-C(S)-;
  • L 1 can be -(CH 2 ) m -, and m can be 1 or 2;
  • each R 1a , R 1b independently can be hydrogen or a C 1-6 aliphatic group optionally substituted by R;
  • each R can be hydrogen
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -S- or -(R 2 )N-;
  • X may be -L 1 -C(R 1a )(R 1b )-C(O)-;
  • L 1 can be -(C(R 3a )(R 3b )) m -, m can be 0, 1 or 2,
  • R 2 can be a C 1-6 aliphatic group
  • each of R 1a , R 1b , R 3a , and R 3b can each independently be hydrogen or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -S- or -(R 2 )N-;
  • X may be -L 1 -C(R 1a )(R 1b )-C(O)-;
  • L 1 can be -(C(R 3a )(R 3b )) m -, and m can be 1 or 2;
  • R 2 can be a C 1-6 aliphatic group
  • each of R 1a , R 1b , R 3a , and R 3b can each independently be hydrogen or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -S- or -(R 2 )N-;
  • X may be -L 1 -C(R 1a )(R 1b )-C(O)-;
  • L 1 can be -(C(R 3a )(R 3b )) m -, and when m can be 0, 1 or 2,
  • R 2 can be a C 1-6 aliphatic group
  • R 1a , R 1b , R 3a , and R 3b can independently be hydrogen or C 1-6 aliphatic group
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 can be -(C(R 3a )(R 3b )) 2 -;
  • each R 3a , R 3b can be hydrogen, or C 1-6 aliphatic group independently;
  • Each of R 3a , R 3b may not be hydrogen at the same time, or 1 methylene unit of L 1 may be replaced by -C(O)-;
  • each R 3a , R 3b can each independently be hydrogen, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 may be -(C(R 3a )(R 3b )) 2 -;
  • each R 3a , R 3b can be hydrogen, or C 1-6 aliphatic group independently;
  • Each of R 3a , R 3b may not be hydrogen at the same time, or 1 methylene unit of L 1 may be replaced by -C(O)-;
  • each R 3a , R 3b can each independently be hydrogen, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -S- or -(R 2 )N-;
  • X may be -L 1 -C(R 1a )(R 1b )-C(O)-;
  • L 1 can be -(C(R 3a )(R 3b )) m -, and when m can be 0, 1 or 2,
  • R 2 can be a C 1-6 aliphatic group
  • R 1a , R 1b , R 3a , and R 3b can independently be hydrogen or C 1-6 aliphatic group
  • L 1 may be -C(R 3a )(R 3b )-, and in each -C(R 3a )(R 3b )-, R 3a and R 3b may be hydrogen at different times;
  • each of R 3a , R 3b may independently be hydrogen or C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 may be -(C(R 3a )(R 3b )) 2 -;
  • each R 3a , R 3b can be hydrogen, or C 1-6 aliphatic group independently;
  • R 3a , R 3b may not be hydrogen at the same time, or 1 methylene unit of L 1 may be replaced by -C(O)-;
  • each R 3a , R 3b can each independently be hydrogen, or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 can be -(CH 2 ) 2 -;
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 may be -(C(R 3a )(R 3b )) m -, m may be selected from an integer from 1 to 5, and in each -C(R 3a )(R 3b )- R 3a , R 3b are not At the same time, it can be hydrogen;
  • each R 3a , R 3b independently can be hydrogen, halogen or a C 1-6 aliphatic group optionally substituted by R;
  • each R can be hydrogen or halogen.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 1 -CH 2 -C(O)-;
  • L 1 may be -C(R 3a )(R 3b )-, and R 3a and R 3b may not be hydrogen at the same time;
  • each of R 3a , R 3b may independently be hydrogen or C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O- or -(R 2 )N-
  • X can be -L 1 -L 0 -;
  • L 1 may be -(CH 2 ) m -, and m may be selected from an integer from 0 to 2;
  • R 2 may be a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -NH-
  • X can be -L 1 -L 0 -;
  • L 1 may be -(CH 2 ) m -, and m may be selected from an integer from 0 to 2;
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -S-, or -(R 2 )N-;
  • X can be -L 3 -L 2 -,
  • L 2 can be -C(O)-
  • L 3 can be -(CH 2 ) n -, and n can be 4 or 5;
  • One methylene unit of L 3 can be replaced by -NR 8 -, -O-, -S- or -SO-;
  • R 2 may be a C 1-6 aliphatic group.
  • R 1 can be -S- or -(R 2 )N-;
  • X can be -L 3 -L 2 -,
  • L 2 can be -C(O)-
  • L 3 can be -(CH 2 ) n -, and n can be 4 or 5;
  • R 2 may be a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 3 -L 2 -,
  • L 2 can be -C(O)-
  • L 3 can be -(C(R 7a )(R 7b )) n -, and n can be 4 or 5;
  • each of R 7a , R 7b , and R 8 can each independently be hydrogen, or a C 1-6 aliphatic group.
  • R 1 can be -O-
  • X can be -L 3 -L 2 -,
  • L 2 can be -C(O)-
  • L 3 may be -(C(R 7a )(R 7b )) 4 -;
  • 1 methylene unit of L 3 can be replaced by -NR 8 - or -O-;
  • each of R 7a , R 7b , and R 8 can each independently be hydrogen or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -O-
  • X can be -L 3 -L 2 -,
  • L 2 can be -C(O)-
  • L 3 may be -(C(R 7a )(R 7b )) 4 -;
  • each of R 7a , R 7b , and R 8 can each independently be hydrogen or a C 1-6 aliphatic group.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or Its pharmaceutically acceptable salt, wherein the compound may comprise the structure represented by formula (III-A):
  • R 1 can be -NH-
  • X can be -L 3 -L 2 -,
  • L 2 can be -C(O)-
  • L 3 can be -(CH 2 ) n -, and n can be 4 or 5;
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a mixture thereof, or A pharmaceutically acceptable salt thereof, wherein the compound may comprise the structure of the following group:
  • R 2 can be a C 1-6 aliphatic group that can be optionally substituted by R, and R can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or a C 1-6 aliphatic group; or wherein R 2 can be halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O )H, or
  • R 2 can be a group that can be replaced by one or more of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH2 , -OC(O)H, -N(H) SO2H , or methyl optionally substituted with a C1-6 aliphatic group.
  • R 2 can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O )C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , - OC(O)H, -N(H) SO2H , or C1-6 aliphatic optionally substituted ethyl.
  • R 2 can be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O )C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , - OC(O)H, -N(H) SO2H , or C1-6 aliphatic optionally substituted propyl.
  • the application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a A pharmaceutically acceptable salt, which may comprise the structure represented by formula (I-B):
  • X a can be the nitrogen generated by the removal of two hydrogen atoms from the amino group of the cytotoxic drug
  • the L can be -L a -L b -L c -;
  • the -L a - may be selected from the following group:
  • W can be -(C(R wa )(R wb )) wn -
  • Y can be -(OCH 2 CH 2 ) yn -O yp -
  • Z can be -(C(R za )(R zb ) ) zn ;
  • wn can be selected from an integer greater than 0,
  • yn can be selected from an integer greater than 0, and yp can be 0 or 1;
  • zn can be selected from an integer greater than 0,
  • -Cyr- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring base, wherein the -Cyr- is unsubstituted or independently may be substituted by more than 1 substituent R cx ;
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , - SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O )R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), - OC(O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic
  • each R r , R ra , R rb can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - may be selected from the following group:
  • R L1 and R L2 can each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • R 1 , L 1 , L 2 are as defined in any one of formula (IA) in the embodiments of the first aspect.
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its pharmaceutically acceptable salt, it can comprise the structure shown in formula (II-Bx) or formula (II-By):
  • X a can be the nitrogen generated by the removal of two hydrogen atoms from the amino group of the cytotoxic drug
  • the L can be -L a -L b -L c -;
  • the -L a - may be selected from the following group:
  • W can be -(C(R wa )(R wb )) wn -
  • Y can be -(OCH 2 CH 2 ) yn -O yp -
  • Z can be -(C(R za )(R zb ) ) zn ;
  • wn can be selected from an integer greater than 0,
  • yn can be selected from an integer greater than 0, and yp can be 0 or 1;
  • zn can be selected from an integer greater than 0,
  • -Cyr- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring base, wherein the -Cyr- is unsubstituted or independently may be substituted by more than 1 substituent R cx ;
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , - SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O )R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), - OC(O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic
  • each R r , R ra , R rb can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - may be selected from the following group:
  • R L1 and R L2 can each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • L 2 , p, Ring A, X 1 , L 1 are as defined in any of the embodiments of the first aspect of formula (II-Ax);
  • X 2 , q, ring A, X 1 , L 1 are as defined in any of the embodiments of the first aspect of formula (II-Ay).
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its pharmaceutically acceptable salt, it can comprise the structure shown in formula (III-B):
  • X a can be the nitrogen generated by the removal of two hydrogen atoms from the amino group of the cytotoxic drug
  • the L can be -L a -L b -L c -;
  • the -L a - may be selected from the following group:
  • W can be -(C(R wa )(R wb )) wn -
  • Y can be -(OCH 2 CH 2 ) yn -O yp
  • Z can be -(C(R za )(R zb )) zn ,;
  • wn can be selected from an integer greater than 0,
  • yn can be selected from an integer greater than 0, and yp can be 0 or 1;
  • zn can be selected from an integer greater than 0,
  • -Cyr- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring base, wherein the -Cyr- is unsubstituted or independently may be substituted by more than 1 substituent R cx ;
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , - SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O )R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), - OC(O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic
  • each R r , R ra , R rb can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the -L c - may be selected from the following group:
  • R L1 and R L2 can each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, - CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, and C 1-6 aliphatic groups;
  • R 1 , X are as defined in any one of formula (III-A) in the embodiments of the first aspect.
  • wn may be selected from an integer from 2 to 6
  • 0 or 1 methylene unit of W may each independently be replaced by -Cyr-, -N( Rwx )C(O)- , -C(O)N( Rwx )-, -C(O)-, -NRwx- , or -O- instead.
  • one methylene unit of W can each independently be replaced by -Cyr-, -N(R wx )C(O)-, -C(O)N( R wx )-, or -C(O)- substitution.
  • yn may be selected from an integer from 0 to 12, and yp may be 0 or 1.
  • yn can be 0, 4 or 8 and yp can be 0 or 1.
  • each of 0 or 1 methylene unit of Z may be independently -Cyr-, -N(R zx )C(O)- , -C(O)N(R zx )-, or -C(O)- substitution.
  • one methylene unit of Z can each independently be replaced by -Cyr-, -N( Rzx )C(O)-, -C(O)N( Rzx )-, or -C(O)- substitution.
  • -Cyr- may be selected from the group consisting of 6 to 10 membered arylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsaturated Substituted or independently may be substituted with 1 to 3 substituents R cx .
  • -Cyr- can be a 3 to 10 membered saturated carbocyclylene, wherein the -Cyr- is unsubstituted or independently substituted with 1 to 3 substituents R cx .
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C (O)CH 2 C(O)R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC(O)R r , -N(R)SO 2 R r , or a C 1-6 alipha
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, halogen, -OR r or C 1-6 optionally substituted by R r an aliphatic group; wherein each R r can independently be hydrogen, halogen, or a C 1-6 aliphatic group.
  • the -L b - represents a peptide residue consisting of 2 to 7 amino acids
  • the peptide residue of -L b - may be formed from amino acids that may be selected from the group consisting of The peptide residues: phenylalanine, glycine, alanine, valine, citrulline, lysine, serine, glutamic acid, and aspartic acid.
  • the -L b - represents a peptide residue composed of 2 to 4 amino acids
  • the peptide residue of the -L b - may be a peptide residue that may be formed from amino acids that may be selected from the group consisting of: benzene Alanine, Glycine, Alanine, Valine, Citrulline and Lysine.
  • the -L b - may be selected from the following group:
  • the -L b - can be
  • the -L c - may be selected from the group consisting of:
  • the -Lc- may be selected from the group consisting of:
  • the -L c - can be
  • R L1 , R L2 can each independently be selected from the group consisting of hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO2H , -C(O)C(O)H, -C(O) CH2C (O)H, -S(O)H, -S(O ) 2H , -C (O) NH2 , -SO2NH2 , -OC(O)H, -N(H) SO2H , and C1-6 aliphatic groups.
  • R L1 , R L2 can each independently be selected from the group consisting of hydrogen, halogen, -OH and C 1-6 aliphatic groups.
  • -L b - may be selected from the group consisting of:
  • -L b - can be selected from the following group:
  • -L c - can be
  • -L a -L b -L c - can be selected from the group consisting of:
  • cytotoxic drug is shown in formula (EXA):
  • the present application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a compound thereof.
  • a pharmaceutically acceptable salt which may comprise the structure represented by formula (I-C):
  • L can be -L a -L b -L c -, and L a , L b , and L c are as defined in any formula (IB) in the embodiments of the second aspect;
  • R 1 , L 1 , L 2 are as defined in any one of formula (IA) in the embodiments of the first aspect.
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its pharmaceutically acceptable salt, it can comprise the structure shown in formula (II-Cx) or formula (II-Cy):
  • L can be -L a -L b -L c -, and L a , L b , and L c are as defined in any of the formulas (II-Bx) in the embodiments of the second aspect;
  • L 2 , p, Ring A, X 1 , L 1 are as defined in any of the embodiments of the first aspect of formula (II-Ax);
  • X 2 , q, ring A, X 1 , L 1 are as defined in any of the embodiments of the first aspect of formula (II-Ay).
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, Or its pharmaceutically acceptable salt, it can comprise the structure shown in formula (III-C):
  • L can be -L a -L b -L c -, and L a , L b , and L c are as defined in any one of the formulae (III-B) in the embodiments of the second aspect;
  • R 1 , X are as defined in any one of formula (III-A) in the embodiments of the first aspect.
  • the present application provides a compound or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a compound thereof.
  • a pharmaceutically acceptable salt which may comprise the structure shown in formula (I-D):
  • Ab can be a ligand, and the average number of connections Na can be an integer or decimal from 1 to 10;
  • L may be -L a -L b -L c -, L a , L b , L c as defined in any of the embodiments of the second aspect of formula (IB);
  • R 1 , L 1 , L 2 are as defined in any one of formula (IA) in the embodiments of the first aspect.
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise a structure represented by formula (II-Dx) or formula (II-Dy)
  • Ab can be a ligand, and the average number of connections Na can be an integer or decimal from 1 to 10;
  • L may be -L a -L b -L c -, L a , L b , L c as defined in any one of formulae (II-Bx) in the embodiments of the second aspect;
  • L 2 , Ring A, X 1 , L 1 are as defined in any of the embodiments of the first aspect of formula (II-Ax);
  • the present application provides a compound or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which may comprise the structure represented by formula (III-D)
  • Ab can be a ligand, and the average number of connections Na can be an integer or decimal from 1 to 10;
  • L may be -L a -L b -L c -, L a , L b , L c as defined in any one of the embodiments of the second aspect of formula (III-B);
  • R 1 , X are as defined in any one of formula (III-A) in the embodiments of the first aspect.
  • the ligand Ab can be an antibody or an antigen-binding fragment thereof.
  • the ligand Ab can be selected from the group consisting of chimeric antibodies, humanized antibodies, and fully human antibodies.
  • the ligand Ab targets the following group: HER2, HER3, B7H3, TROP2, Claudin 18.2, CD30, CD33, CD70 and EGFR.
  • the ligand Ab targets the following group:
  • the antibody may be an antibody targeting the following targets: 5T4, AGS-16, ANGPTL4, ApoE, CD19, CTGF, CXCR5, FGF2, MCPT8, MFI2, MS4A7, NCA, Sema5b, SLITRK6, STC2, TGF, 0772P, 5T4, ACTA2, ADGRE1, AG-7, AIF1, AKR1C1, AKR1C2, ASLG659, Axl, B7H3, BAFF-R, BCMA, BMPR1B, BNIP3, C1QA, C1QB, CA6, CADM1, CCD79b, CCL5, CCR5, CCR7, CD1lc, CD123, CD138, CD142, CD147, CD166, CD19, CD19, CD22, CD21, CD20, CD205, CD22, CD223, CD228, CD25, CD30, CD33, CD37, CD38, CD40, CD45, CD45 (PTPRC
  • the average number of connections Na may be an integer or decimal from 2 to 8.
  • the average number of connections Na may be an integer or decimal from 3 to 8.
  • the average number of connections Na may be an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10 .
  • the present application provides a compound represented by the general formula (I-E) or a tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 , L 1 , and L 2 are as defined in any one of formula (IA) in the embodiments of the first aspect.
  • the present application provides a compound represented by general formula (II-E x ) or general formula (II-E y ) or its tautomer, meso, racem isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:
  • L 2 , p, ring A, X 1 , L 1 are as defined in any one of the formulae (II-Ax) in the embodiments of the first aspect;
  • X 2 , q, ring A, X 1 , L 1 are as defined in any of the embodiments of the first aspect of formula (II-Ay).
  • the present application provides a compound represented by the general formula (III-E) or its tautomer, meso, racemate, enantiomer, non-pair An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 , X are as defined in any one of formula (III-A) in the embodiments of the first aspect.
  • the present application provides a compound represented by general formula (I-F) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • the L x can be -L ax -L b -L c -;
  • the Lax- may be selected from the following group:
  • R hal can be iodine or bromine
  • W can be -(C(R wa )(R wb )) wn -
  • Y can be -(OCH 2 CH 2 ) yn -O yp -
  • Z can be -(C(R za )(R zb ) ) zn ;
  • wn can be selected from an integer greater than 0,
  • yn can be selected from an integer greater than 0, and yp can be 0 or 1;
  • zn can be selected from an integer greater than 0,
  • -Cyr- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring base, wherein the -Cyr- is unsubstituted or independently may be substituted by more than 1 substituent R cx ;
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , - SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O )R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), - OC(O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic
  • each R r , R ra , R rb can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • L b , L c are as defined in any one of formula (IB) in the embodiments of the second aspect;
  • R 1 , L 1 , L 2 are as defined in any one of formula (IA) in the embodiments of the first aspect.
  • the present application provides a compound represented by general formula (II-F x ) or general formula (II-F y ) or its tautomer, meso, and racemate , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:
  • the L x can be -L ax -L b -L c -;
  • the Lax- may be selected from the following group:
  • R hal can be iodine or bromine
  • W can be -(C(R wa )(R wb )) wn -
  • Y can be -(OCH 2 CH 2 ) yn -O yp -
  • Z can be -(C(R za )(R zb ) ) zn ;
  • wn can be selected from an integer greater than 0,
  • yn can be selected from an integer greater than 0, and yp can be 0 or 1;
  • zn can be selected from an integer greater than 0,
  • -Cyr- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring base, wherein the -Cyr- is unsubstituted or independently may be substituted by more than 1 substituent R cx ;
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , - SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O )R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), - OC(O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic
  • each R r , R ra , R rb can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • L b , L c are as defined in any one of the formulae (II-Bx) in the embodiments of the second aspect;
  • L 2 , p, ring A, X 1 , L 1 are as defined in any one of the formulae (II-Ax) in the embodiments of the first aspect;
  • X 2 , q, ring A, X 1 , L 1 are as defined in any of the embodiments of the first aspect of formula (II-Ay).
  • the present application provides a compound represented by general formula (III-F) or its tautomer, meso, racemate, enantiomer, non-pair An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:
  • the L x can be -L ax -L b -L c -;
  • the Lax- may be selected from the following group:
  • R hal can be iodine or bromine
  • W can be -(C(R wa )(R wb )) wn -
  • Y can be -(OCH 2 CH 2 ) yn -O yp -
  • Z can be -(C(R za )(R zb ) ) zn ;
  • wn can be selected from an integer greater than 0,
  • yn can be selected from an integer greater than 0, and yp can be 0 or 1;
  • zn can be selected from an integer greater than 0,
  • -Cyr- may be selected from the group consisting of: 6- to 10-membered arylene, 5- to 8-membered heteroarylene, 3- to 10-membered heterocyclylene, and 3- to 10-membered saturated or partially unsaturated carbocyclic ring base, wherein the -Cyr- is unsubstituted or independently may be substituted by more than 1 substituent R cx ;
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , - SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C(O)CH 2 C(O )R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), - OC(O)R r , -N(R)SO 2 R r , or a C 1-6 aliphatic
  • each R r , R ra , R rb can be independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C(O)H, -CO 2 H, -C(O)C(O)H, -C(O)CH 2 C(O)H, -S(O)H, -S(O) 2 H, -C(O)NH 2 , -SO 2 NH 2 , -OC(O)H, -N(H)SO 2 H, or C 1-6 aliphatic group;
  • L b , L c are as defined in any one of formula (III-B) in the embodiments of the second aspect;
  • R 1 , X are as defined in any one of formula (III-A) in the embodiments of the first aspect.
  • the Lax- may be selected from the group of:
  • R hal can be iodine or bromine
  • W can be -(C(R wa )(R wb )) wn -
  • Y can be -(OCH 2 CH 2 ) yn -O yp -
  • Z can be -(C(R za )(R zb ) ) zn .
  • wn may be selected from an integer from 2 to 6
  • 0 or 1 methylene unit of W may each independently be replaced by -Cyr-, -N( Rwx )C(O)- , -C(O)N( Rwx )-, -C(O)-, -NRwx- , or -O- instead.
  • one methylene unit of W can each independently be replaced by -Cyr-, -N(R wx )C(O)-, -C(O)N( R wx )-, or -C(O)- substitution.
  • yn may be selected from an integer from 0 to 12, and yp may be 0 or 1.
  • yn can be 0, 4 or 8 and yp can be 0 or 1.
  • each of 0 or 1 methylene unit of Z may be independently -Cyr-, -N(R zx )C(O)- , -C(O)N(R zx )-, or -C(O)- substitution.
  • one methylene unit of Z can each independently be replaced by -Cyr-, -N( Rzx )C(O)-, -C(O)N( Rzx )-, or -C(O)- substitution.
  • -Cyr- may be selected from the group consisting of 6 to 10 membered arylene, and 3 to 10 membered saturated or partially unsaturated carbocyclylene, wherein -Cyr- is unsaturated Substituted or independently may be substituted with 1 to 3 substituents R cx .
  • -Cyr- can be a 3 to 10 membered saturated carbocyclylene, wherein the -Cyr- is unsubstituted or independently substituted with 1 to 3 substituents R cx .
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR r , -SR r , -N(R ra )(R rb ), -C(O)R r , -CO 2 R r , -C(O)C(O)R r , -C (O)CH 2 C(O)R r , -S(O)R r , -S(O) 2 R r , -C(O)N(R ra )(R rb ), -SO 2 N(R ra )(R rb ), -OC(O)R r , -N(R)SO 2 R r , or a C 1-6 alipha
  • each R wa , R wb , R za , R zb , R wx , R zx , R cx can each independently be hydrogen, halogen, -OR r or C 1-6 optionally substituted by R r an aliphatic group; wherein each R r can independently be hydrogen, halogen, or a C 1-6 aliphatic group.
  • Lax - can be
  • Lax - Lb - Lc- can be selected from the group of:
  • the compounds disclosed herein include, but are not limited to:
  • the average number of connections n in the above list can be an integer or decimal from 1 to 10.
  • the average number of connections n in the above list can be an integer or decimal from 2 to 8.
  • the average number of connections n may be an integer from 3 to 8 or a decimal.
  • the average number of connections n may be an integer or decimal from 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, and 9 to 10.
  • the compounds disclosed herein include, but are not limited to:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Cell Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
PCT/CN2021/121721 2020-09-30 2021-09-29 一种抗肿瘤化合物及其制备方法和应用 WO2022068878A1 (zh)

Priority Applications (17)

Application Number Priority Date Filing Date Title
CN202211407530.9A CN115925796B (zh) 2020-09-30 2021-09-29 一种抗肿瘤化合物及其制备方法和应用
EP21874533.9A EP4223318A1 (en) 2020-09-30 2021-09-29 Antitumor compound, and preparation method therefor and use thereof
KR1020237011470A KR20230079085A (ko) 2020-09-30 2021-09-29 항종양 화합물 및 그의 제조 방법 및 용도
AU2021354823A AU2021354823A1 (en) 2020-09-30 2021-09-29 Antitumor compound, and preparation method therefor and use thereof
CN202310152789.1A CN116239601B (zh) 2020-09-30 2021-09-29 一种抗肿瘤化合物及其制备方法和应用
CN202211403184.7A CN116199739A (zh) 2020-09-30 2021-09-29 一种抗肿瘤化合物及其制备方法和应用
CN202180018263.3A CN115175705A (zh) 2020-09-30 2021-09-29 一种抗肿瘤化合物及其制备方法和应用
MX2023003778A MX2023003778A (es) 2020-09-30 2021-09-29 Compuesto antitumoral, metodo de preparacion y uso del mismo.
CA3195515A CA3195515A1 (en) 2020-09-30 2021-09-29 Anti-tumor compound and preparation method and use thereof
IL301793A IL301793A (en) 2020-09-30 2021-09-29 Anticancer compound and method for its preparation and use
JP2023520181A JP2023551355A (ja) 2020-09-30 2021-09-29 抗腫瘍化合物並びにその調製方法及び使用
US17/825,090 US11685742B2 (en) 2020-09-30 2022-05-26 Anti-tumor compound and preparation method and use thereof
US17/828,433 US11607459B1 (en) 2020-09-30 2022-05-31 Anti-tumor compound and preparation method and use thereof
US18/147,070 US11952384B2 (en) 2020-09-30 2022-12-28 Anti-tumor compound and preparation method and use thereof
US18/187,935 US20230331738A1 (en) 2020-09-30 2023-03-22 Anti-tumor compound and preparation method and use thereof
US18/495,455 US20240132516A1 (en) 2020-09-30 2023-10-26 Anti-tumor compound and preparation method and use thereof
US18/506,610 US20240174686A1 (en) 2020-09-30 2023-11-10 Anti-tumor compound and preparation method and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011061580.7 2020-09-30
CN202011061580 2020-09-30

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/825,090 Continuation US11685742B2 (en) 2020-09-30 2022-05-26 Anti-tumor compound and preparation method and use thereof

Publications (1)

Publication Number Publication Date
WO2022068878A1 true WO2022068878A1 (zh) 2022-04-07

Family

ID=80951198

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/121721 WO2022068878A1 (zh) 2020-09-30 2021-09-29 一种抗肿瘤化合物及其制备方法和应用

Country Status (11)

Country Link
US (6) US11685742B2 (ja)
EP (1) EP4223318A1 (ja)
JP (1) JP2023551355A (ja)
KR (1) KR20230079085A (ja)
CN (3) CN116239601B (ja)
AU (1) AU2021354823A1 (ja)
CA (1) CA3195515A1 (ja)
IL (1) IL301793A (ja)
MX (1) MX2023003778A (ja)
TW (1) TW202214230A (ja)
WO (1) WO2022068878A1 (ja)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023088235A1 (en) * 2021-11-16 2023-05-25 Genequantum Healthcare (Suzhou) Co., Ltd. Exatecan derivatives, linker-payloads, and conjugates and thereof
WO2023138635A1 (zh) * 2022-01-18 2023-07-27 甘李药业股份有限公司 一种依喜替康衍生物-抗体偶联物及其医药用途
WO2023143365A1 (zh) * 2022-01-28 2023-08-03 映恩生物制药（苏州）有限公司 Her3抗体药物偶联物及其用途
WO2023173026A1 (en) * 2022-03-10 2023-09-14 Sorrento Therapeutics, Inc. Antibody-drug conjugates and uses thereof
WO2023174401A1 (zh) * 2022-03-18 2023-09-21 映恩生物制药（苏州）有限公司 Gpc3抗体药物偶联物及其用途
WO2023216956A1 (zh) * 2022-05-13 2023-11-16 四川科伦博泰生物医药股份有限公司 喜树碱类化合物及其制备方法和应用
WO2023217064A1 (zh) * 2022-05-09 2023-11-16 同宜医药（苏州）有限公司 一种喜树碱衍生物，基于其的抗体-药物偶联物和药物组合物，及其应用
WO2023236949A1 (zh) * 2022-06-07 2023-12-14 映恩生物制药（苏州）有限公司 抗b7h3抗体-药物偶联物及其用途
WO2024022165A1 (zh) * 2022-07-29 2024-02-01 杭州爱科瑞思生物医药有限公司 依沙替康衍生物及其应用
WO2024026323A1 (en) * 2022-07-26 2024-02-01 Zeno Management, Inc. Immunoconjugates and methods
WO2024049931A1 (en) 2022-09-02 2024-03-07 Merck Sharp & Dohme Llc Exatecan-derived topoisomerase-1 inhibitors pharmaceutical compositions, and uses thereof
WO2024067811A1 (en) * 2022-09-30 2024-04-04 Beigene, Ltd. Ligand-drug conjugate of exatecan analogue, and medical use thereof
WO2024078449A1 (en) * 2022-10-09 2024-04-18 LaNova Medicines Limited Compounds, compositions and methods
WO2024091437A1 (en) 2022-10-25 2024-05-02 Merck Sharp & Dohme Llc Exatecan-derived adc linker-payloads, pharmaceutical compositions, and uses thereof
US11999748B2 (en) 2021-11-16 2024-06-04 Genequantum Healthcare (Suzhou) Co., Ltd. Exatecan derivatives, linker-payloads, and conjugates and thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3195515A1 (en) * 2020-09-30 2022-04-07 Duality Biologics (Suzhou) Co., Ltd. Anti-tumor compound and preparation method and use thereof
WO2024098066A1 (en) * 2022-11-04 2024-05-10 ALX Oncology Inc. Exatecan derivatives and antibody-drug conjugates thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104755494A (zh) 2012-10-11 2015-07-01 第一三共株式会社 抗体-药物偶联物
CN105829346A (zh) * 2014-01-31 2016-08-03 第三共株式会社 抗her2抗体－药物偶联物
US20170035906A1 (en) * 2014-04-10 2017-02-09 Daiichi Sankyo Company, Limited (anti-her2 antibody)-drug conjugate
CN109789211A (zh) * 2016-10-07 2019-05-21 第一三共株式会社 基于抗her2抗体-药物偶联物施予的耐性癌的治疗
WO2020063673A1 (zh) * 2018-09-30 2020-04-02 江苏恒瑞医药股份有限公司 抗b7h3抗体-依喜替康类似物偶联物及其医药用途
WO2020063676A1 (zh) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 依喜替康类似物的配体-药物偶联物及其制备方法和应用
CN111689980A (zh) * 2019-05-26 2020-09-22 四川百利药业有限责任公司 一种喜树碱药物及其抗体偶联物
WO2021007435A1 (en) * 2019-07-10 2021-01-14 Cybrexa 2, Inc. Peptide conjugates of cytotoxins as therapeutics

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR240698A1 (es) 1985-01-19 1990-09-28 Takeda Chemical Industries Ltd Procedimiento para preparar compuestos de 5-(4-(2-(5-etil-2-piridil)-etoxi)benzil)-2,4-tiazolidindiona y sus sales
WO2014061277A1 (ja) * 2012-10-19 2014-04-24 第一三共株式会社 親水性構造を含むリンカーで結合させた抗体－薬物コンジュゲート
CN109106951A (zh) 2017-08-18 2019-01-01 四川百利药业有限责任公司 一种喜树碱-抗体偶联物
EP3876998A1 (en) 2018-11-05 2021-09-15 Synaffix B.V. Antibody-conjugates for targeting of tumours expressing trop-2
AU2020347715A1 (en) 2019-09-18 2022-04-07 Baili-Bio (Chengdu) Pharmaceutical Co., Ltd. Camptothecin derivative and conjugate thereof
CA3195515A1 (en) * 2020-09-30 2022-04-07 Duality Biologics (Suzhou) Co., Ltd. Anti-tumor compound and preparation method and use thereof
CN114456186B (zh) 2020-10-12 2023-10-20 成都百利多特生物药业有限责任公司 一种喜树碱类衍生物及其配体-药物偶联物
WO2022078279A1 (zh) 2020-10-12 2022-04-21 昆山新蕴达生物科技有限公司 抗体-药物偶联物及其应用
CN114569739A (zh) 2020-12-01 2022-06-03 正大天晴药业集团股份有限公司 抗体药物偶联物
EP4289851A1 (en) 2021-02-05 2023-12-13 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Camptothecin compound, preparation method therefor, and application thereof
CN113816969B (zh) 2021-04-30 2024-01-16 联宁（苏州）生物制药有限公司 依喜替康类化合物、其抗体药物偶联物及其应用
AU2022269073A1 (en) 2021-05-07 2023-11-23 ALX Oncology Inc. Exatecan derivatives and antibody-drug conjugates thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104755494A (zh) 2012-10-11 2015-07-01 第一三共株式会社 抗体-药物偶联物
CN105829346A (zh) * 2014-01-31 2016-08-03 第三共株式会社 抗her2抗体－药物偶联物
US20170035906A1 (en) * 2014-04-10 2017-02-09 Daiichi Sankyo Company, Limited (anti-her2 antibody)-drug conjugate
CN109789211A (zh) * 2016-10-07 2019-05-21 第一三共株式会社 基于抗her2抗体-药物偶联物施予的耐性癌的治疗
WO2020063676A1 (zh) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 依喜替康类似物的配体-药物偶联物及其制备方法和应用
WO2020063673A1 (zh) * 2018-09-30 2020-04-02 江苏恒瑞医药股份有限公司 抗b7h3抗体-依喜替康类似物偶联物及其医药用途
CN111689980A (zh) * 2019-05-26 2020-09-22 四川百利药业有限责任公司 一种喜树碱药物及其抗体偶联物
WO2021007435A1 (en) * 2019-07-10 2021-01-14 Cybrexa 2, Inc. Peptide conjugates of cytotoxins as therapeutics

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHOTHIA ET AL.: "Canonical Structures For the Hypervariable Regions of Immunoglobulins", J. MOL. BIOL., vol. 196, 1987, pages 901, XP024010426, DOI: 10.1016/0022-2836(87)90412-8
KABAT E.A. ET AL.: "Sequences of proteins of immunological interest", 1991, NIH
MACCALLUM ET AL.: "Antibody-Antigen Interactions: Contact Analysis and Binding Site Topography", J. MOL. BIOL., vol. 262, 1996, pages 732, XP002242391, DOI: 10.1006/jmbi.1996.0548

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2022393856B2 (en) * 2021-11-16 2023-11-23 Genequantum Healthcare (Suzhou) Co., Ltd. Exatecan derivatives, linker-payloads, and conjugates and thereof
AU2022393856A9 (en) * 2021-11-16 2023-08-24 Genequantum Healthcare (Suzhou) Co., Ltd. Exatecan derivatives, linker-payloads, and conjugates and thereof
US11814394B2 (en) 2021-11-16 2023-11-14 Genequantum Healthcare (Suzhou) Co., Ltd. Exatecan derivatives, linker-payloads, and conjugates and thereof
US11999748B2 (en) 2021-11-16 2024-06-04 Genequantum Healthcare (Suzhou) Co., Ltd. Exatecan derivatives, linker-payloads, and conjugates and thereof
WO2023088235A1 (en) * 2021-11-16 2023-05-25 Genequantum Healthcare (Suzhou) Co., Ltd. Exatecan derivatives, linker-payloads, and conjugates and thereof
WO2023138635A1 (zh) * 2022-01-18 2023-07-27 甘李药业股份有限公司 一种依喜替康衍生物-抗体偶联物及其医药用途
WO2023143365A1 (zh) * 2022-01-28 2023-08-03 映恩生物制药（苏州）有限公司 Her3抗体药物偶联物及其用途
WO2023173026A1 (en) * 2022-03-10 2023-09-14 Sorrento Therapeutics, Inc. Antibody-drug conjugates and uses thereof
WO2023174401A1 (zh) * 2022-03-18 2023-09-21 映恩生物制药（苏州）有限公司 Gpc3抗体药物偶联物及其用途
WO2023217064A1 (zh) * 2022-05-09 2023-11-16 同宜医药（苏州）有限公司 一种喜树碱衍生物，基于其的抗体-药物偶联物和药物组合物，及其应用
WO2023216956A1 (zh) * 2022-05-13 2023-11-16 四川科伦博泰生物医药股份有限公司 喜树碱类化合物及其制备方法和应用
WO2023236949A1 (zh) * 2022-06-07 2023-12-14 映恩生物制药（苏州）有限公司 抗b7h3抗体-药物偶联物及其用途
WO2024026323A1 (en) * 2022-07-26 2024-02-01 Zeno Management, Inc. Immunoconjugates and methods
WO2024022165A1 (zh) * 2022-07-29 2024-02-01 杭州爱科瑞思生物医药有限公司 依沙替康衍生物及其应用
WO2024049931A1 (en) 2022-09-02 2024-03-07 Merck Sharp & Dohme Llc Exatecan-derived topoisomerase-1 inhibitors pharmaceutical compositions, and uses thereof
WO2024067811A1 (en) * 2022-09-30 2024-04-04 Beigene, Ltd. Ligand-drug conjugate of exatecan analogue, and medical use thereof
WO2024078449A1 (en) * 2022-10-09 2024-04-18 LaNova Medicines Limited Compounds, compositions and methods
WO2024091437A1 (en) 2022-10-25 2024-05-02 Merck Sharp & Dohme Llc Exatecan-derived adc linker-payloads, pharmaceutical compositions, and uses thereof

Also Published As

Publication number Publication date
KR20230079085A (ko) 2023-06-05
JP2023551355A (ja) 2023-12-08
US11607459B1 (en) 2023-03-21
CN116199739A (zh) 2023-06-02
US20240174686A1 (en) 2024-05-30
US11952384B2 (en) 2024-04-09
CN116239601B (zh) 2023-10-13
AU2021354823A1 (en) 2023-03-30
MX2023003778A (es) 2023-04-26
US20230331738A1 (en) 2023-10-19
CN115175705A (zh) 2022-10-11
CA3195515A1 (en) 2022-04-07
TW202214230A (zh) 2022-04-16
US11685742B2 (en) 2023-06-27
CN115925796A (zh) 2023-04-07
US20240132516A1 (en) 2024-04-25
US20230086097A1 (en) 2023-03-23
CN116239601A (zh) 2023-06-09
US20230212182A1 (en) 2023-07-06
IL301793A (en) 2023-05-01
EP4223318A1 (en) 2023-08-09

Similar Documents

Publication Publication Date Title
WO2022068878A1 (zh) 一种抗肿瘤化合物及其制备方法和应用
TWI826543B (zh) 依喜替康類似物的配體-藥物偶聯物、其製備方法及其應用
CN112125915A (zh) 一种喜树碱衍生物及其偶联物
CN106573956A (zh) 澳瑞他汀衍生物及其缀合物
TW201718025A (zh) 抗體藥物偶聯物的共價鍵連接子及其製備方法與應用
WO2021190581A1 (zh) 一种含抗体药物偶联物的药物组合物及其用途
WO2021190602A1 (zh) 一种抗体药物偶联物的制备方法
CN112839683A (zh) 含有标记部-抗人抗体Fab片段复合物的药物组合物
WO2023143365A1 (zh) Her3抗体药物偶联物及其用途
WO2023138635A1 (zh) 一种依喜替康衍生物-抗体偶联物及其医药用途
WO2023186015A1 (zh) B7h4抗体药物偶联物及其用途
CN114306635A (zh) 包含可裂解接头的化合物及其用途
WO2023174401A1 (zh) Gpc3抗体药物偶联物及其用途
CN114569739A (zh) 抗体药物偶联物
CN111542324B (zh) 细胞毒性剂及其偶联物、其制备方法及用途
WO2022262789A1 (zh) 一种抗肿瘤化合物及其应用
CN115925796B (zh) 一种抗肿瘤化合物及其制备方法和应用
WO2023232142A1 (zh) 一种药物化合物及其用途
WO2022228494A1 (zh) 抗体偶联药物的制备方法及应用
WO2023207710A1 (zh) 一类抗体药物偶联物、其药物组合物及应用
CN118079013A (zh) 稠环类化合物及其偶联物和用途
CN117430660A (zh) 奥瑞他汀f类似物及其抗体药物偶联物与应用
WO2024006542A1 (en) Anti-ror1 antibodies and antibody conjugates, compositions comprising anti-ror1 antibodies or antibody conjugates, and methods of making and using anti-ror1 antibodies and antibody conjugates
IL307317A (en) A toxic dimer compound of DNA and its conjugate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21874533

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3195515

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2023520181

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2021354823

Country of ref document: AU

Date of ref document: 20210929

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023005846

Country of ref document: BR

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021874533

Country of ref document: EP

Effective date: 20230502

ENP Entry into the national phase

Ref document number: 112023005846

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20230329

WWE Wipo information: entry into national phase

Ref document number: 523440061

Country of ref document: SA